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  • 1
    Online Resource
    Online Resource
    Tau spreads across connected brain regions in progressive supranuclear palsy and corticobasal syndrome
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S4 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Cortico‐basal degeneration (CBD) and progressive supranuclear palsy (PSP) are 4R‐tauopathies characterized by progressive tau pathology spread that typically starts in the subcortex. Pre‐clinical studies suggest that tau spreads across connected neurons in an activity‐dependent manner, indicating that the brains’ connectome may mediate tau spreading. Supporting this, we found in Alzheimer’s disease that PET‐assessed cortical tau spreads across functionally connected regions. Here, we assessed whether connectivity mediates cortical/subcortical tau spreading also in 4R‐tauopathies, by combining resting‐state fMRI connectivity with i) 2 nd generation in vivo tau‐PET (PI2620) in CBS and PSP and ii) post‐mortem tau assessments in PSP. Method We assessed PI2620 tau‐PET in 24 CBS‐patients, 28 PSP‐patients and 15 healthy controls. Voxel‐wise tau‐PET differences were determined between patients vs. controls and mean tau‐PET SUVRs were assessed for 232 cortical/subcortical‐ROIs (Fig. 1A). Semi‐quantitative post‐mortem AT8‐stained neuronal tau was assessed in two additional, non‐overlapping PSP samples (Munich: n=96; & UPENN: n=97). Neuropathological ROIs were reconstructed in MRI‐standard‐space (Figs. 1B & C). Functional connectivity was assessed between tau‐PET‐ROIs and neuropathological‐ROIs using out‐of‐sample resting‐state fMRI from 69 elderly amyloid‐ and tau‐negative controls. Using linear regression, we assessed the association between ROI‐to‐ROI connectivity and covariance in tau‐PET or post‐mortem tau levels in spatially corresponding ROI pairs. For tau‐PET, we further tested at the subject level, whether functional connectivity of tau epicenters (i.e. ROIs with highest tau‐PET in a given subject) predicted tau deposition in connected regions, using linear mixed models controlling for age, gender and random intercept. Result PSP and CBS patients showed elevated tau‐PET compared to controls (Fig. 2). Higher functional connectivity was associated with higher covariance in tau‐PET in PSP and CBS (b=0.402‐0.715, Fig. 3A‐D, all p 〈 0.001). For post‐mortem data, higher ROI‐to‐ROI functional connectivity was also associated higher covariance in tau in both PSP samples (b=0.468 & 0.765, p 〈 0.001, Fig. 3E & F). Using tau‐PET we found further that connectivity patterns of subject‐level subcortical tau epicenters was associated with subject‐level tau‐PET uptake in connected regions (Fig. 4B‐E, all p 〈 0.001). Conclusion Highly functionally connected brain regions share similar tau levels in 4R‐tauopathies as indicated by tau‐PET and post‐mortem assessments, suggesting that brain connectivity is associated with inter‐regional tau spreading in 4R‐tauopathies.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S4
    DOI: 10.1002/alz.051668
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 2
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    Online Resource
    Empirical pathological staging and subtyping of TDP‐43 proteinopathies
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S4 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
    Abstract: Pathological aggregation of tar DNA‐binding protein 43 (TDP‐43) in the brain is the primary cause of many cases of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). It is therefore imperative to establish empirical staging systems to characterize and distinguish stereotypical patterns and commonplace deviations of different TDP‐43 proteinopathies. Method We use ordinal ratings of TDP‐43 burden from 19 brain regions to perform data‐driven disease progression modeling (SuStaIn) to find the most likely trajectories for FTLD‐TDP (n = 108), ALS (n = 137) and LATE (n = 283) from the CNDR Brain Bank at the University of Pennsylvania. Subtype number was defined using cross‐validated information criterion. Each individual was assigned a subtype and stage. Multivariate OLS models tested differences between subtypes. Stages were compared to age and existing staging schemes. Cross‐validated logistic regression was used for 3‐way classification using SuStaIn information only. Result SuStaIn provided data‐driven staging of TDP‐43 proteinopathies complementing previously described human‐defined staging schema, further providing additional detail (Fig1A‐C; Fig3A‐C). SuStaIn also identified two distinct subtypes within FTLD‐TDP and a further two within ALS (Fig1D). FTLD‐TDP subtypes differed in TDP‐43 type and Alzheimer’s disease pathology (Table1); ALS subtypes were differentiated by age (Table 2) and by antemortem clinical characteristics. No subtypes were observed for the LATE group. Progression along data‐driven stages was positively associated with age in LATE individuals, but negatively associated with age in individuals with FTLD‐TDP (Fig2). Using only regional TDP‐43 severity, our data driven model could distinguish individuals diagnosed with ALS, FTD or LATE with a cross‐validated balanced precision of 0.93 and balanced recall of 0.92, and these metrics improved to 0.95 and 0.96 when combined with a logistic regression model (Fig3). Very little stage overlap was found between FTLD‐TDP and LATE, but stages that did overlap showed subtly different patterns (Fig4) Conclusion We provide an empirical pathological staging system for ALS, FTLD‐TDP and LATE, which is sufficient for staging and accurate classification. We demonstrate that there is substantial heterogeneity amongst ALS and FTLD‐TDP progression patterns, whilst LATE exhibits a homogeneous progression pattern.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S4
    DOI: 10.1002/alz.063390
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 3
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    Online Resource
    A consensus proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation : Molecular and cell biology/others
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. S2 ( 2020-12)
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    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S2 ( 2020-12)
    Abstract: Our understanding of the biological changes in the brain associated with Alzheimer’s disease (AD) pathology and cognitive impairment remains incomplete. Unbiased discovery proteomic analysis of AD brain can help to increase our understanding of these changes. Method We analyzed dorsolateral prefrontal cortex, precuneus, and temporal cortex of control, asymptomatic AD, and AD brains from multiple different centers by label‐free quantitative mass spectrometry and weighted protein co‐expression analysis to obtain a consensus protein co‐expression network of AD brain. We also analyzed cerebrospinal fluid to investigate potential biomarkers related to this network. Result The network consisted of 13 protein co‐expression modules. Six of these modules correlated with amyloid‐β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These six modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community‐based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module. This module was enriched in AD genetic risk factors, and was also highly enriched in microglia and astrocyte protein markers associated with an anti‐inflammatory state, suggesting that the biological functions it represents may serve a protective role in AD. Proteins from the sugar metabolism module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network. Conclusion In this study of 〉 2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S2
    DOI: 10.1002/alz.039504
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 4
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    Online Resource
    THE EFFECT OF CHLORTETRACYCLINE ON AUSTRALIAN PARROTS NATURALLY INFECTED WITH PSITTACOSIS
    Wiley ; 1961
    In:  Medical Journal of Australia Vol. 2, No. 4 ( 1961-07), p. 134-139
    Details
    In: Medical Journal of Australia, Wiley, Vol. 2, No. 4 ( 1961-07), p. 134-139
    Type of Medium: Online Resource
    ISSN: 0025-729X , 1326-5377
    URL: Issue
    URL: Article
    DOI: 10.5694/mja2.1961.2.issue-4
    DOI: 10.5694/j.1326-5377.1961.tb24354.x
    Language: English
    Publisher: Wiley
    Publication Date: 1961
    detail.hit.zdb_id: 2035730-8
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  • 5
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    Online Resource
    ATN classifications in a mixed cohort of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) pathology using cerebrospinal fluid neurofilament light chain (NFL) : Biomarkers (non‐neuroimaging) / Differential diagnosis
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. S5 ( 2020-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S5 ( 2020-12)
    Abstract: The ATN framework combines cerebrospinal fluid (CSF) amyloidβ 1‐42 (Aβ 1‐42 ), phosphorylated tau (p‐tau), and total tau (t‐tau) to diagnose individuals along the continuum of Alzheimer’s disease (AD). While ATN profiles indicative of AD are highly accurate, profiles indicating normal, non‐AD pathology, or concurrent AD and non‐AD pathology are inconsistent, due in part to the insensitivity of t‐tau to non‐AD pathologies, such as frontotemporal lobar degeneration (FTLD). We test a modified framework that replaces t‐tau with neurofilament light chain (NFL), a CSF marker of axonal degeneration. Method We compare ATN classifications using t‐tau (ATNt) and NFL (ATNf) in an pathology‐confirmed autopsy cohort of 72 AD (3 with concurrent FTLD) and 26 FTLD (14 with concurrent low‐high AD). In an independent living sample, receiver operating characteristic (ROC) analyses defined an optimal NFL cut‐point using 18 hereditary FTLD (10 C9ORF72 , 3 MAPT, 2 progranulin, and 3 TARDBP) and 27 matched control subjects without cognitive impairment. Published cut‐points (Shaw et al., 2009) defined A (Aβ 1‐42 〈 192 pg/mL), T (p‐tau 〉 23 pg/mL), and Nt (t‐tau 〉 93 pg/mL) status, and the above ROC‐threshold (NFL 〉 1003 pg/mL) defined Nf status to create a CSF‐based ATNt and ATNf profile for each patient. Result ATNt and ATNf were equally likely to identify Alzheimer’s continuum disease based on Aβ 1‐42 . Fisher’s test indicated no difference in Nf‐positivity (41 of 72) and Nt‐positivity (44 of 72) for AD pathology ( p =0.73). ATNf correctly identified 25 of 26 FTLD cases as non‐AD pathology; 21 FTLD cases were classified as non‐AD (A‐T‐Nf+/A‐T+Nf+), 4 as non‐AD and concurrent AD (A+T‐Nf+), and 1 misclassified as normal (A‐T‐Nf‐). Fisher’s test showed that ATNf was significantly more likely to identify FTLD as non‐AD pathology than ATNt (OR = 152.9, CI = 16 – 7639, p 〈 0.001); under ATNt, only 3 FTLD cases were classified as non‐AD (A‐T‐Nt+/A‐T+Nt+), while 19 were misclassified as normal (A‐T‐Nt‐) and 4 as early AD pathologic change (A+T‐Nt‐). Conclusion ATNf designations using NFL were more accurate than t‐tau when assessing a mixed AD‐FTLD pathology cohort. Future biomarker strategies to detect both AD and non‐AD neuropathologies, such as FTLD, should consider alternative markers for N.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S5
    DOI: 10.1002/alz.039144
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2201940-6
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  • 6
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    Online Resource
    Unfolding the medial temporal lobe to characterize neurodegeneration due to Alzheimer's disease pathology
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S4 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Measurements of medial temporal lobe (MTL) neurodegeneration derived using MRI have been shown to be sensitive to changes during the early stages of AD. The specificity of these measurements to tau neurofibrillary tangle (NFT) pathology is limited by other frequently comorbid non‐AD factors which also cause structural changes in the MTL. Here, we directly link changes in MTL structure to underlying NFT pathology by combining ex vivo MRI with ratings of NFT severity derived from serial histology using a dataset of 18 human MTL specimens. We hypothesize that such an analysis can be used to define MTL “hotspots” where in vivo measures will be more sensitive to disease progression in preclinical AD than current state of the art biomarkers. Method Ex vivo specimens from 18 donors were scanned at 0.2x0.2x0.2mm 3 on 9.4T MRI. Following MRI scanning, the specimens underwent histological processing with staining for cytoarchitecture and in 15 specimens, immunohistochemistry (IHC) with the anti‐tau AT8 antibody. Using a topological unfolding method (DeKraker et al. 2018), we created 2D representations of the extra‐hippocampal cortex which implicitly align cortical folding patterns across specimens (Fig. 1). An average MTL subregion segmentation was generated in unfolded space using manual segmentations completed in 11 specimens on the basis of cytoarchitecture. Additionally, heat maps quantifying NFT burden in each of the specimens with anti‐tau IHC sections were generated using a deep learning algorithm (Yushkevich et al. 2021). Using the heatmaps and the average subregion segmentation, we investigated the relationship between NFT severity and cortical thickness. Result Correlation analysis between NFT measures and thickness (correcting for age) reveals strong associations in the entorhinal cortex and the border of Brodmann Area 35, consistent with the early Braak regions, and parts of Brodmann Area 36 (Fig. 2). Conclusion We present an unfolding framework applied to the MTL cortex, which allows us to visualize, for the first time, the distribution of MTL subregions and NFT pathology in an unfolded space. This framework provides a promising tool for detailed investigation of structural changes due to NFT pathology while explicitly accounting for the complex topology of the MTL, thereby enhancing our understanding of early AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S4
    DOI: 10.1002/alz.057622
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 7
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    Online Resource
    Short Telomeres Associate with Hyperphosphorylated Tau Burden in Primary Age‐Related Tauopathy
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S3 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S3 ( 2022-12)
    Abstract: Primary age‐related tauopathy (PART) is characterized by neuropathological hyperphosphorylated tau burden (p‐tau) in the absence of significant amyloid pathology. Aging is a major risk factor for p‐tau that is generally defined chronologically in years since birth. Telomeres shorten with age and various sources of DNA damage and thus telomere lengths (TL) provide an alternative measure of biological age. Additionally, DNA methylation (DNAm) changes over time and may contribute to changes in TL. Together, we hypothesize that shorter mean TL will be associated with increased risk of p‐tau burden and that this process may be mediated by DNAm. Method We extracted DNA from frontal cortex of 113 individuals (Age=87.3+9.3; 37% Female) that met neuropathological criteria for definite PART. We measured mean TL using qPCR to determine the copy number of telomere repeat DNA in comparison to a single copy gene. The assays were performed in a blinded fashion, and each sample was measured using two different amounts of input DNA to ensure linearity. We also measured bisulfite‐converted DNA methylation using the Illumina MethylationEPIC BeadChip Kit for ∼850K CpGs. P‐tau burden was measured in medial temporal cortex (entorhinal cortex and hippocampus proper) using an Aperio Digital Pathology Slide Scanner. Linear regression related TL to p‐tau burden, adjusting for age. We used eWAS to relate methylation to TL. Lastly, non‐parametric bootstrapping using the mediation package in R was used to evaluate whether TL association with p‐tau burden may be mediated by DNAm. Result Shorter TL was significantly associated with increased p‐tau burden (B=‐0.28; p=‐.003), including adjustment for age (B=0.003; p=0.003). eWAS identified six CpG sites significantly associated with TL (all q 〈 0.05). Causal mediation analyses identified that two of these CpGs partially mediate the association between TL length and p‐tau burden: 32.5% proportion mediated by cg08701686 ( UNC5D ) and 48.6% proportion mediated by cg24533059 (near IFNGR1 and OLIG3 ). Conclusion Shorter TL is associated with increased p‐tau pathological burden in PART and may be mediated in part by DNAm at particular loci. These findings support the concept that biological aging, as measured with TL and DNAm, may contribute to tauopathy beyond chronological age effects.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S3
    DOI: 10.1002/alz.067329
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 8
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    Online Resource
    Modules of genotypic variance reflect heterogeneity across TDP‐43 proteinopathies
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S4 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
    Abstract: TAR DNA‐binding protein (TDP‐43) proteinopathies yield a variety of neurodegenerative conditions including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and hippocampal sclerosis of aging (HS‐Aging). However, the contribution of both shared and disparate single nucleotide polymorphisms (SNPs) to phenotypic presentations is unclear. We hypothesize that shared genetic variation may drive susceptibility across diseases while disparate genetic variation may contribute to our understanding of disease‐specific drivers. Method We compared the relative associations of GWAS summary statistics for ALS, FTLD‐TDP, and HS‐Aging using weighted correlation analysis to identify data‐driven modules of highly correlated SNPs. A gene ontology enrichment analysis for biological processes was performed separately for each identified module. Enrichment was determined by overrepresentation test. Module SNPs were used to construct polygenic risk scores (PRS). PRS were tested for association with neuropathological diagnosis in an independent sample of autopsy‐confirmed individuals. Result We identified 493,591 SNPs commonly genotyped across ALS, FTLD‐TDP, and HS‐Aging GWAS summary statistics, and the top 1% of these were selected for analysis. We identified five modules: three modules associated with a single GWAS phenotype, ALS (M1, containing 1,907 SNPs), FTLD‐TDP (M2, containing 1,727 SNPs), and HS‐Aging (M3, containing 1,031 SNPs), as well as two modules associated with the phenotypic pairs, ALS‐FTLD (M4, 140 SNPs) and FTLD‐HS (M5, containing 129 SNPs). The top 10 overrepresented pathways by fold enrichment that met FDR p 〈 .05 include processes related to nervous system development, including neuron projection and axon guidance, and the regulation of synapse organization and assembly in M1‐ALS and M2‐FTLD‐TDP. Notably, M1‐ALS uniquely includes pathways involved in skeletal muscle satellite cell activation as well as metabolic processes, which have known dysfunction in ALS. Pathways related to neurogenesis were uniquely observed in M3‐HS‐Aging. A PRS was calculated for M1‐ALS and we observed a significantly higher dosage of risk in a neuropathologically‐defined sample of primary ALS (n=131) than primary FTLD‐TDP cases (n=110; d=.27, p=.04). Conclusion Examining genotypes revealed modules of both shared and disparate correlated SNPs across phenotypes associated with TDP‐43 proteinopathies which have biologically plausible pathway and neuropathological associations. We suggest that genetic variation across TDP‐43 proteinopathies may contribute to individual‐level presentations of these syndromes.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S4
    DOI: 10.1002/alz.066820
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 9
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    Online Resource
    Deep Learning for Ultra High Resolution T2‐weighted 7 Tesla Ex vivo Magnetic Resonance Imaging Reveals Differential Subcortical Atrophy across Neurodegenerative Diseases
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: Ex vivo magnetic resonance imaging (MRI) of the brain provides remarkable advantages over in vivo MRI for linking neuroanatomy and morphometry to underlying pathology (Yushkevich et al. 2021, Ravikumar et al. 2021). Subcortical structures show atrophy in certain neurodegenerative diseases, especially Frontotemporal Lobar Degeneration with TDP‐43 (FTLD‐TDP) and four‐repeat (4R) tauopathies (i.e., Corticobasal Degeneration, Progressive Supranuclear Palsy) (Miletić et al. 2022), yet few methods exist to measure subcortical atrophy in ex vivo MRI. We present a framework to quantify subcortical morphometry using 7 Tesla ex vivo MRI and distinguish atrophy patterns across neurodegenerative spectrums. Method A deep learning method, nnU‐Net (Isensee et al. 2021), was trained on manual segmentations from only 3 brain hemispheres to obtain automated segmentations of 4 subcortical structures (caudate, putamen, globus pallidus, thalamus) across 38 subjects spanning Alzheimer's Disease (AD), Lewy Body Disease (LBD), FTLD‐TDP, 4R tauopathies and miscellaneous tauopathies (Figure 1, Table 1). Subcortical volumes were extracted from automated segmentations. Cerebral cortical volume was computed via cortical segmentation method in Khandelwal et al. 2021. Regional volumes were evaluated via likelihood ratio tests (Figure 2), adjusted for covariates (age, sex and intracranial volume from in vivo MRI) and multiple tests. Separately, correlations were computed between subcortical volumes, cortical thicknesses at 18 landmark locations and neuropathological ratings (Khandelwal et al. 2021, Wisse et al. 2021, Figure 3). Result The pipeline validated regional volumetric relationships in neurodegeneration. Global cortex volume did not significantly differ among disease groups (Figure 2). Compared to AD, FTLD‐TDP had significantly lower putamen and thalamus volumes while 4R tauopathies had reduced putamen and caudate volumes ( P ’s 〈 0.05, adjusted for covariates/multiple comparisons). Before multiple tests correction, there were decreased covariate‐adjusted volumes in globus pallidus and caudate in FTLD‐TDP and thalamus in 4R tauopathy relative to AD. Subcortical volumes correlated with each other ( P ’s 〈 0.05) but not with cortical thickness, with trends in motor cortex (Figure 3). Subcortical volumes also trended with local tau pathology (Figure 4). Conclusion Our ex vivo neuroimaging framework differentiates subcortical atrophy patterns in FTLD‐TDP and 4R tauopathies compared to AD, highlighting utility in ex vivo imaging for diagnosing and investigating neurodegeneration.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.062628
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 10
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    Combining high‐resolution ex vivo MRI and histopathology to identify medial temporal lobe atrophy patterns specific to tau pathology in Alzheimer’s Disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S6 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: Tau pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is an early pathological change associated with Alzheimer’s disease (AD). MRI measures of MTL neurodegeneration have proven to be sensitive to change during preclinical AD. Current measures are confounded by the presence of non‐AD pathologies (e.g., TDP‐43, ageing). Here, we combine ex vivo imaging with histopathological ratings of tau and TDP‐43 to identify fine‐grained MTL atrophy patterns specific to tau. Such an analysis could be used to define MTL “hotspots” where in vivo measures of neurodegeneration are expected to be strongly associated with tau, potentially enabling the development of biomarkers that are more effective during early AD clinical trials. Method Ex vivo MRI scans (0.2x0.2x0.2mm 3 , 9.4T) of human MTL specimens were combined using a customized registration approach to construct a 3D atlas. Using serial histology available in a subset of specimens (n = 11), MTL subregions in the atlas were labelled based on cytoarchitecture (Ravikumar et al., 2021) (Figure 1A). To perform thickness analysis, 29 specimens containing a primary diagnosis of AD or primary age‐related tauopathy were registered to the atlas (13 specimens were registered to the atlas during atlas construction, and 16 were registered to the atlas after it was constructed) (Figure 1B, Table 1). Using histopathology measures of tau and TDP‐43 pathology (based on contralateral sampling), we investigated the association between tau and thickness by fitting a linear model (with age/TDP‐43 as covariates) at each point along the MTL and SRLM surface. Result Pointwise thickness analysis reveals significant atrophy patterns in the transentorhinal region and SRLM. When excluding age from the model, stronger tau associations are observed in the SRLM, entorhinal cortex, and extending further towards Brodmann Area 35 (Figure 2). Conclusion Our findings are consistent with early Braak stages but suggest that covarying for age may be obscuring some associations due to tau since age and tau burden have a highly correlated relationship (Figure 3). In future work, quantitative maps of NFT burden will be mapped from serial pathology images into atlas space, allowing us to characterize NFT distribution in 3D (Yushkevich et al., 2021).
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S6
    DOI: 10.1002/alz.065784
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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